Synthesis of tryptophane



. Patented Aug. 24, 1948 UNITED STATES PATENT OFFICE SYNTHESIS OFTRYPTOPHANE Harold R. Snyder, Urbana, 111., and Eugene E. Howe, Linden,and Arthur J. Zamblto, Railway, N. 3., assignors to Merck 8: 00., Inc.,lltahway,

N. 3., a corporation of New Jersey No Drawing.

Application October 21, 1944, Serial No. 559,836

16 Claims. (Cl. 260-319) This invention relates generally to processesfor producing dl-trytophane, and particularly to a new process forpreparing intermediates useful in preparing dl-tryptophane.

dl-Tryptophane has been heretofore prepared by condensingindole-3-aldehyde with hydantoin or hippuric acid. According to a newsynthesis,

for dl-tryptophane fully disclosed in a companion joint application byone of the present applicants filed concurrently with this application(Serial NO. 559,837 filed October 21, 1944) an' alkali metal derivativeof an acylamidomalonic ester is condensed with a quaternary substitutedB-aminomethyl-indole such as, for example, gramine methiodide. to formas an intermediate the corresponding ester of. thea-acylamido-acarboxy-p- (3-indole) -propionic acid. This intermediate isconverted to dl-tryptophane by deesterification, decarboxylation, anddeacetylation.

It is now discovered according to the present invention that thisintermediate and related compounds can be prepared without resorting toThe condensation is efiected by heat alone, fusion of the reactants, orby heating in a suitable organic solvent such as, for example, toluene,

xylene, pyridine and dioxane, the latter method being more satisfactoryespecially from the standpoint of control of the reaction. Even betteryields and a purer product are obtained by carrying out the condensationin solvents in the presence of a basic catalyst. Suitable catalysts forthis purpose are alkali and alkaline earth metals, their hydroxides,carbonates, and alcothe quaternary ammonium salt and alkali metal R1 0 0OR: R4

CHr-N HC-N OORi R COOK: R4

where R1 and R2 each represent an alkyl, aryl or aralkyl radical, or R1and R2 together form part of a N-heterocyclic radical, Ra represents analkyl, aryl, or aralkyl radical, R4 represents an acyl radical, R5represents hydrogen or an'acyl radical, or R4 and Rs may be adicarboxylic organic acid radical.

holates. It is also found that the amount of air or oxygen to which thereaction is exposed affacts the yield and purity of the product. Bestresults are obtained by carrying out the condensation in an oxygen-freeatmosphere by circulating through the reaction chamber an inert gas suchas, for example, nitrogen.

The following examples illustrate methods of carrying out the presentinvention but it is to be understood that these examples are given byway of illustration and not of limitation.

Example I To a mixture of about 17 g. of powdered sodium hydroxide and1275 cc. of toluene heated to reflux with agitation is added a mixtureof about 250g. of gramine and about 311 g. of ethyl acetamidomalonate inan oxygen-free atmosphere. The mixture is then refluxed for about 5hours with agitation and maintaining a flow of an inert gas through themixture. The hot reaction mixture is then filtered and cooled, causingthe separation of ethyl-a-acetamido-a-carbethoxyfi-(3-indole) propionate(M. P. 158-159 C.) which is removed by filtration and purified byconventional operations.

Example II A mixture of 19.7 g. of gramine, 24.5 g. of ethylacetamidomalonate and cc. of pyridine is refiuxedjor about.2 hours in anoxygen-free atmosphere. The resulting mixture is treated with activatedcarbon, filtered, concentrated to a volume of about 50 cc., and dilutedwith about 20 cc. of water. This mixture is then held at about 5 C. forabout 6 hours, after which an additional 80 cc.".of water is added andthe mixture maintained at approximately 5 C. for an additional 18 hours.The precipitated ethyl-a-acetamidoa-carbethoxy -,3- (3-indole)propionate (M. P; l57-158 C.) so obtained is removed by filtration.

Example III To about 24.5 g. of ethyl acetamidomalonate at C. is addedabout 19.7 g. of gramine over a 3 period of about to minutes. Thetemperature is raised during this addition to about 165 C. and ismaintained at this temperature for about 10 minutes after of the gramineis added. The resulting red oily product is cooled to about 70 0.,dissolved in 70 cc. of ethanol, and then diluted with about 50 cc. ofwarm water. This solution is cooled at about 5 C. for approximately 18hours, causing precipitation of the ethyl-a-acetamido-a carbethoxyp-(3-indole) propionate (M. P. 157-158 C.) which is removed byfiltration.

Example IV To a boiling mixture 01' 150 cc. of toluene and 2 g. ofpowdered sodium hydroxide in an oxygenfree atmosphere is added, withagitation, about 36.8 g. of ethyl acetamidomaionate and about 34.4 g. ofp-(diethylaminomethyl)-indole. The reaction mixture is then refluxedwith agitation for about 2 hours while maintaining the inert atmosphere.The reflux reaction mixture is then filtered. and the filtrate cooled toabout 5 C. for several hours causing the separation ofethyl-aacetamido-e-carbethoxy-p- (ii-indole) propionate (M. P. 156-158C.) which is removed by filtration.

Example V About 2.45 g. of ethyl acetamidomalonate and about 2.42 g. ofB-(N-piperidyl-methyl) -indole are condensed in a reaction mediaconsisting of 10 cc. of toluene and g. of powdered sodium hydroxide,refluxed, and the product, ethyl oracetamido-a-carbethoxy-p-(ii-indole)propionate (M. P. 157-158" 0.), is obtained using the procedure employedin the preceding Example IV.

Example VI sodium hydroxide as a catalyst in the condensation isdescribed, it is understood that the condensation proceeds in the samemanner when other basic catalysts previously enumerated are substitutedfor sodium hydroxide. Likewise, the condensation proceeds in the mannerindicated when other solvents, previously identified, are substitutedfor the solvents employed in the examples.

It should also be noted that while N-alkyl substituted3-aminomethyl-indole compounds. and compounds-wherein the N-substituentsform a N-heterocyclic radical (piperidyl radical), are referred to inthe examples, aryl substituted compounds such as3-diphenylaminomethyl-indole and aralkyl compounds such as3-dibenzylaminomethyl-indole can be employed. The by-product aminecompounds formed in the condensation, when low boiling as in the case ofdimethylamine or diethylam ine, are removed from the reaction mixture inthe gaseous state during condensation. When these by-product amines arehigh boiling as in the case of piperidine diphenylamine ordibenzylamine, they remain in the solvent and are thus separated fromthe precipitated condensation product.

The process is described in the examples using ethyl acetamidomalonateand ethyl phthalimidomalonate in the condensation. It is understood,however, that compounds having other alkyl as well as aryl and aralkylester groups and other N -acyl substituents can be employed. Thus, otherstarting materials are compounds such as methyl acetamidomalonate, ethylacetamidomalonate, phenyl acetamidomalonate, benzyl acetamidomalonate,and the like, and corresponding esters of other acylamidomalonic acidssuch as formamidomalonic acid, benzamidomalonic acid, phthalimidomalonicacid and the like. The products obtained by condensing these compoundswith atertiary substituted 3-aminomethyl-indole are methyl, ethyl,phenyl or benzyl esters of a-formamido-a carboxy-p- (3 indole) propionicacid, a-aeetamido-a-carboxy-p-(3-indole) propionic acid,a-be'nzamido-a-carboxy p -(3-indole) -propionic acid, andm-DhthfllilnldO-oz-Ciifboxy-fi-(3-indole)-propionic acid. Thesecompounds are converted to dl-tryptophane as previously described bydeesterification, decarboxylation, and deacetylation.

By the term acylamido as employed in the following claims is meant: anamido group of the class consisting of mono-acylamido and di-acylamidogroups, including groups wherein the acyl substituents are linked by analkyl or an aryl grouping. It is alsoto be understood that the estersreferred to in the specification and claims are the (ii-esters. 1

Modifications may be made in carrying out the present invention withoutdeparting from the spirit and scope thereof, and the invention is to belimited only by the appended claims.

What is claimed is:

1. The process that comprises condensing a 3-aminomethyl indole compoundwith an unsubstituted ring nitrogen and having tertiary N-substituentsselected from the class consisting of alkyl, aryl, and aralkyl groupsand groups wherein the substituents form part of a N-heterocyclicradical with an acylamidomalonic ester having an active hydrogen on thecentral carbon atom,

.thereby forming the corresponding ester of a-acylamido-a-carboxy-B-(Ii-indole) -propionic acid.

2. The process that comprises condensing a 3-aminomethyl indole compoundwith an unsubstituted ring nitrogen and having tertiary N-substituentsselected from the class consisting of alkyl, aryl, and aralkyl groupsand groups wherein the substituents form part of a N-heterocyclicradical with an aeylamidomalonic ester having an active hydrogen on thecentral carbon atom, in an oxygen-free atmosphere, thereby forming thecorresponding ester of a-acylamido-a-carboxy-B- (3-indole) -propionicacid.

3. The process that comprises condensing a 3-aminomethyl indole compoundwith an unsubstituted ring nitrogen and having tertiary N-substituentsselected from the classconsisting of alkyl, aryl, and aralkyl groups andgroups wherein the substituents form part of a N-heterocyclic radicalwith an acylamidomalonic ester having an active hydrogen on the centralcarbon atom, by heating a mixture thereof, thereby forming thecorresponding ester of a-acylamido-a-carboxyan active hydrogen on thecentral carbon atom, in the presence of a non-reactive organic liquidwhich is a solvent for the starting materials, thereby forming thecorresponding ester of a-acylamido-a-carboxy fl-(3-indole)-propionicacid.

5. The process that comprises condensing a 3-aminomethyl indole compoundwith an unsubstituted ring nitrogen and having tertiary N-substituentsselected from the class consisting of alkyl, aryl, and aralkyl groupsand groups wherein the substituents form part of a N-heterocyelicradical with an acylamldomalonlc ester having an active hydrogen on thecentral carbon atom, in the presence of a non-reactive organic liquidwhich is a solvent for the starting materials while maintaining anoxygen-free atmosphere, thereby forming the corresponding ester ofa-acylamidoa-CflrbOXY-fi- (3-indole) -propionlc acid.

6. The process that comprises condensing a B-aminomethyl indole compoundwith an unsubstituted ring nitrogen and having tertiary N-substituentsselected from the class consisting of alkyl, aryl, and aralkyl groupsand groups wherein the substituents form part of a N-heterocyclicradical with an acylamidomalonic ester having an active hydrogen on thecentral carbon atom, in the presence of a non-reactive organic liquidwhich is a solvent for the starting materials and a basic catalyst ofthe class consisting of alkali and alkaline earth metals, theirhydroxides, carbonatcs, and alcoholates, thereby forming thecorresponding ester of a-flCYlfimldO-a-CRIIJOXY-{i- (3-indole)-proplonic acid.

7. The process that comprises condensing a 3-aminomethyl indole compoundwith an unsubstituted ring nitrogen and having tertiary N-substituentsselected from the class consisting of alkyl, aryl, and aralkyl groupsand groups wherein the substituents form part of a N-heterocyclicradical with an acylamidomalonic ester having an active hydrogen on thecentral carbonatom, in the presence of a non-reactive organic liquidwhich is a solvent for the starting materials and a basic catalyst ofthe class consisting of alkali and alkaline earth metals, theirhydroxides, carbonates, and alcoholates while maintaining an oxygen freeatmosphere, thereby forming the corresponding ester ofa-acylamido-a-carboxy-B- (El-indole) -propionic acid. v

8. The process that comprises condensing graminc with ethylacetamidomalonate thereby forming ethyl a-acetamido-a-carbethoxy-p-(3-indole) -propionate.

9. The process that comprises condensing gramine with ethylacetamidomalonate in the presence of toluene and a small amount ofsodium hydroxide as a catalyst while maintaining an oxygen-freeatmosphere thereby forming ethyl a-acetamido-a-carbethoxy-p -(3-indole)propionate.

10. The process that comprises condensing 3-diethylaminomethyl indolewith ethyl acetamidomalonate thereby forming ethyla-acetamido-a-carbethoxy-fi-(3-indole) -proplonate.

11. The process that comprises condensing 3-dlethylaminomethyl indolewith 'ethyl acetamidomalonate in the presence of toluene and a smallamount of sodium hydroxide as a catalyst while maintaining anoxygen-free atmosphere thereby forming ethyla-acetamido-a-carbethoxyli-i B-indole) -propionate.

12. The process that comprises condensing 3-piperidylaminomethyl indolewith ethyl acetamidomalonate thereby forming ethyla-acetamido-e-carbethoxy-fl-(3-indole) -propionatc.

13. The process that comprises condensing B-piperidylaminomethyl indolewith ethyl acetamidomalonate in the presence of toluene and a smallamount of sodium hydroxide as a catalyst while maintaining anoxygen-free atmosphere thereby forming ethylcat-3C8tfililidO-a-CZtl'b8th0Xy-- (B-indole) -propionate.

14. The process that comprises condensing a B-aminomethyl indolecompound with an unsubstituted ring nitrogen and having tertiary N-substituents selected from the class consisting of alkyl, aryl, andaralkyl groups and groups wherein the substituents form part of aN-heterocyclic radical with an acylamidomalonic ster having an activehydrogen on the'central carbon atom, in a nitrogen atmosphere, therebyforming the corresponding ester of a-acylamido-a-carboxy-;i-(3- indole)-propionic acid.

15. The process that comprises condensing a 3aminomethyl indole compoundwith an unsubstituted ring nitrogen and having tertiary N-substituentsselected from the class consisting of alkyl, aryl, and aralkyl groupsand groups wherein the substituents form part of a N-heterocyclicradical with an acylamidomalonic ester having an active hydrogen on thecentral carbon atom, in

the presence of a non-reactive organic liquid which is a solvent for thestarting materials while maintaining a nitrogen atmosphere, therebyforming the corresponding ester of a-acylamidoa-carboxy-fl-(ii-indole)-propionic acid.

16. The process that comprises condensing 3-aminomethyl-indole compoundwith an unsubstituted ring nitrogen and having tertiary N-sub stituentsselected from the class consisting of alkyl, aryl, and aralkyl groupsand groups wherein the substituents form part of a N-heterocyclicradical with an acylamldomalonic ester having an active hydrogen on thecentral carbon atom, in the presence of a non-reactive organic liquidwhich is a solvent for the starting materials and a basic catalyst ofthe class consisting of alkali and alkaline earth metals, theirhydroxides, carbonates, and alcoholates-in a nitrogen atmosphere,thereby forming the corresponding ester of m-acyl- 'amido-u-carboxy-p-(3-indole) -propionic acid.

HAROLD R. SNYDER. EUGENE E. HOWE. ARTHUR J. ZAMBITO.

REFERENCES CITED record in the

